FORMULATION AND EVALUATION OF FAST-DISSOLVING ORAL FILM OF RIVAROXABAN

Abstract

Following the COVID-19 pandemic, microvascular and macrovascular thrombotic problems emerged that required anticoagulants. Rivaroxaban (RN) is a factor Xa inhibitor that treats deep vein thrombosis and the two forms of artery diseases (coronary artery disease and peripheral artery disease). Materials and Methods: The study objective was to create fast-disintegrating rivaroxaban Oral Thin Films (OTF) with the help of various super disintegrants to shorten disintegration time and enhance drug release in order to assist patients who have difficulty in swallowing conventional dosage forms and increase bioavailability. OTF was created using the solvent casting method. A 22 factorial design was employed in Design-Expert• software to develop an ideal formula. Results: The optimized film formula pH, drug content, disintegration time, folding endurance, and dissolution rate were estimated, and the film was subjected to a short-term stability study.

Specification

Description:FIELD OF INNOVATION:
[0001] In this research main goal is to formulate and evaluate fast-dissolving oral film of rivaroxaban.

BACKGROUND:
[0002] The microvascular and the macrovascular thrombotic problems emerged that required anticoagulants. Rivaroxaban (RN) is a factor x. inhibitor that treats deep vein thrombosis and the two forms of artery diseases (coronary artery disease and peripheral artery disease). Materials and Methods: The study objective was to create fast-disintegrating rivaroxaban Oral Thin Films (OTF) with the help of various super disintegrants to shorten disintegration time and enhance drug release in order to assist patients who have difficulty in swallowing conventional dosage forms and increase bioavailability. OTF was created using the solvent casting method. A 22 factorial design was employed in Design-Expert software to develop an ideal formula.

[0003] The optimized film formula pH, drug content, disintegration time, folding endurance, and dissolution rate were estimated, and the film was subjected to a short-term stability study. The optimized formula exhibited a cumulative drug release of 93.47% in 60 sec. Conclusion: The drug's in vitro release pattern shows first-order kinetics and fickian diffusion was the mechanism of drug release. These findings supported that rivaroxaban OTFs offer a quick release of the medication from the administration site into the systemic circulation.

SUMMARY:
[0004] The Oral thin films have a variety of approaches to solve the issues associated with the oral route of administration. Oral thin films are one example of a product in which we utilize super disintegrants to disperse the dosage form.'ll1ese rapid-dissolving drug delivery systems will disperse on the patient's tongue without water or chewing in minutes or seconds.

[0005] A solid dosage from constitutes around 60% of all formulations. The oral route of administration is widely used due to its ease, absence of pain, and versatility.1 Dysphagia affects people of usages, but it is more widespread in older persons. The fear of choking inhibits many paediatric and elderly patients from delivering this solid dosage forms.2 Dysphagia is linked to clinical illnesses such as stroke, head and neck thyroid treatment, Parkinson's disease, thyroidectomy, AIDS, and other neurological issues such as cerebral palsy. the most common concern was tablet size, followed by surface area and flavour.
[0006] Oral thin films are placed on the dorsum or the floor of the tongue. It contains lo the application position, and the drug is absorbed by oral mucosa due to its highly permeable nature into systemic circulation. Due to its high vascularity and permeability, the active substance is delivered for local and systemic uptake. Hydrophilic polymers are chosen since they are easily dissolved when it comes in contact with saliva. This innovative drug delivery method can improve drug solubility/stability, biological half-life, and bioavailability.

[0007] Hydroxypropyl methyl cellulose (HPMC E 15 LV) was used as a film-forming agent. It contains 28-30% methoxy, 7-12% hydroxypropyl. It encompasses thermal gelation with outstanding film characteristics (high tensile strength, strength, and elongation). DOACs (Direct Oral Anti coagulants) have been u ed fur various indications- arterial di eases, heart failure, cancer, and the prevention of DVT in acute medical diseases.

[0008] post-COVID-19 pandemic, it was clear that the, victims have been diagnosed with higher levels of thrombin, fibrin components, and other clotting factors that promote clot formation. This led to an increase in the administration of DOACs. One such anticoagulant is rivaroxaban - a factor X, inhibitor capable of dissolving clots internally and externally with minimal drug-drug or drug-food interactions. Unlike indirect factor X inhibitors such as fondaparinux or heparin, Rivaroxaban suppresses both free and clot-bound factor x. and prothrombinase, which prolongs the clotting time.

[0009] Solvent casting approach was effectively used to prepare oral thin films that were stocked with rivaroxaban. According to FT-IR spectrum the polymer and formulation did not change the functional bands of rivaroxaban. A neutral surface pH of optimised formulation of F5 with smooth surface that was sufficiently elegant to be seen. The dose uniformity test acceptance value requirement had been met by the optimized F5 formulation, which also showed excellent stability and dissolution profile. Based on the finding, it can be said that the optimized formulation F5 offers a quick release of the drug from the site of administration into the systematic circulation, thereby enhancing the bioavailability of rivaroxaban.

DESCRIPTION OF FIGURES AND TABLES:
[0010] Table (1): 22 full factorial design layouts.

[0011] Table (2): Coded value for concentration of polymer (X1) and concentration
of super disintegrant (X2).
[0012] Table (3): Formulation table of Oral thin films using DoE.

[0013] Table (4): Reported and observed FT-IR frequencies of pure drug and physical mixture.

[0014] Table (5): DoE generated 22 factorial designs.

[0015] Table (6): In vitro dissolution studies.

[0016] Table (7): Release Kinetics of Rivaroxaban OTF.

[0017] Table (8): Optimized formulation FS stability studies data for 1 month.

[0018] Figure (1): Standard Graph of Rivaroxaban in Acetonitrile.

[0019] Figure (2): FT-IR spectra of Rivaroxaban.

[0020] Figure (3): FT-IR spectra of physical mixture and Rivaroxaban.

[0021] Figure (4): Thermogram of Rivaroxaban.

[0022] Figure (5): Thermogram of Physical mixture.

[0023] Figure (6): 3D response surface plot of R1 (disintegration time).

[0024]. Figure (7): Contour plot of R2 (Folding Endurance).

[0025] Figure (8): 3D response surface plot of R2 (Folding Endurance).

[0026] Figure (9): 3D response surface plot of R3 (Thickness).

[0027] Figure (10): Contour plot of R3 (Thickness).

[0028] Figure (11): Invitro dissolution studies.

[0029] Figure (12): Overlay plot.

[0030] Figure (13): Invitro dissolution studies.

DETAILED DESCRIPTION:
[0031] Rivaroxaban was received as a gift sample from Alpha med Formulations Pvt. Ltd., Hyderabad. Propylene glycol was obtained from Thermo Fisha Scientific India Pvt. Ltd., Bengaluru. while HPMC was purchased from Loba Chemie Pvt. Ltd., Mumbai. Sodium starch glycolate and aspartame was supplied by Merck, Mumbai. All other chemicals and compounds utilized were of analytical grade.

[0032] The aim of the study is to enhance the bioavailability of rivaroxaban at the receptor site by formulating oral thin films. The reason to enhance bioavailability of oral thin films is Lo overcome the disadvantages of conventional dosage forms. initial stage in the rational development of dosage forms is pre formulation study. It investigates drugs molecular and physical characteristics, both alone and when combined with excipients. Preformulating assessment aims to generate data to help the formulator construct safe, bioavailable, and mass-producible dosage forms.

[0033] Excipient - Drug Compatibility Research Fourier Transforms Infra-Red (FTIR) Spectroscopy: FT-IR spectra (Bruker alpha, Germany) was obtained to discover possible interactions between the drug and polymers. The ingredients were compressed with a hydraulic press to form a pellet (less than 5 k pas). The disc was put in the centre of the sample holding device and spectrum was recorded using an FT-IR spectrophotometer. Differential Scanning Calorimetry (DSC): DSC thermograms of API and physical mixture was recorded by enclosing them in heat-resistant aluminium pans. The surface of the pan lid was crimped by pushing them against a pellet mill. 1he pans were held in the heating chamber to temperatures ranging from 30 to 300 C at l00 C/min.

[0034] Analytical Method Development: Determination of λmax. for rivaroxaban by using acetonitrile: Th.: calibration curve for rivaroxaban was developed using acetonitrile.
Thickness= (Tl+ T2 + T3 + T4 + TS) / 5
Preparation of standard curve for rivaroxaban by using acetonitrile: From the 1000 µg/mL stock solution, l00 µg/mL solution is prepared. Different concentrations or rivaroxaban at various concentrations 2, 4, 6, 8, IO µg/mL were obtained, and its absorbance was determined.

[0035] Preparation of oral Dissolving Film of Rivaroxaban Using 22 Factorial Designs: A two-factor design has been used for optimization Table 1. The independent factors, as well as the dependent variables, were chosen. Three independent variables have been chosen.1 he highest and lowest factor values were marked as +I and -1 Table 2. All samples were quantitatively assessed usu1g ANOVA and Design Expert l software to determine the chosen variable significance and non-significance effect on responses such as disu1tegration time, folding endurance, and thickness. n1c factor impact was visually represented using 30 response surface plots and contour plots in design expert.

[0036] Preparation of rivaroxaban mouth dissolving film: The solvent casting process involves adding I JPMC El 5 LV and propylene glycol to the water, keeping the temperature at 60 C and the stirrer rotating at 1000 rpm. Colour, flavouring agent, sweetening agent, and disintegrant are dissolved in waler with continuous stirring. 1l1e resultant solution is combined with the API dissolved in a solvent. To extract the trapped air, a vacuum is employed. the homogenous solution formed is cast as a film and allowed to dry before being cut into the appropriate size.

[0037] Evaluation of mouth dissolving films of rivaroxaban: Physical appearance and surface texture of films: these criteria were confirmed easily by inspecting films visually and by reel or touch. The finding implies the films surface nature and visually appealing or not.

[0038] Organoleptic analysis: Organoleptic assessment of prepared oral disintegrating films arc performed with the previous agreement of a group of healthy participants with good organoleptic sensibilities. The flavour, tongue feel (grittiness or smoothness), and the oral disintegrating films outward look was evaluated Thickness, the width of the film is proportionate to its dosage uniformity. The ultimate thickness of the film is checked by calculating the mean thickness at five distinct locations with micrometre screw gauge. It should be between 50 mm to 1000 mm.

[0039] Surface pH: the surface pH of the films was evaluated by exposing them to I mL of di tilled water. The surface pH was determined by introducing pH paper dose to the surface of the films.
Average weight= weight of 10 strips / 10

[0040] Folding endurance: Film folding endurance is determined to check the film durability. Folding endurance was determined by repeatedly folding a tiny film strip until it breaks. The endurance value is determined by the number of times it can be folded without tearing.

[0041] Content uniformity: Three films were individually assayed for their drug content. Film was dissolved and diluted with water get a 1 µg/mL concentration. The film must contain APl of 85- I 15% of the label claim to have content uniformity.

[0042] Disintegration time (petri dish method): this technique was carried out on a pelri plate. 1l1e oral thin film was placed in the centre of a petri dish filled with 10 mL of distiller Water. The time taken for the thin layer to disintegrate is measured, and the procedure is done thrice.

[0043] Moisture absorption: The moisture absorption is measured by first dividing the film into 2 x 2 cm2 squares. These strips art' then subjected to a 75% relative humidity atmosphere at room temperature for a week. Moisture absorption is calculated as a percentage weight increase of the strip.

[0044] In vitro dissolution studies: the dissolution study was carried out in a type II USP apparatus. 900 mL of dissolution medium was taken and maintained at 37 C 0.5 C. The film was attached to a rotating centre axis. Filtered samples were taken manually at I5, 30, 45, and 60 sec. At the same temperature, the samples were compensated with an equivalating volume of pure water. After appropriate dilution with the dissolving media, the concentration of the drug released in the medium was measured spectrophotometrically at 249 nm.

[0045] Dissolution parameters: Dissolution apparatus (Type II),
Dissolution Medium: Purified water, 900 ml.
Percentage moisture loss = Initial weight - Final weight x 100 / Initial weight
RPM: 50, Temperature: 370 C ±0.50 C, Withdrawal time: I 5, 30, 45 and 60 sec,
Volume withdrawal: 5 mL.

[0046] Release kinetics: The amount of drug released from the pharmaceutical dosage form and its processes is an essential but which is intricate process in metro systems. Zero order or first order kinetics were used to characterize the sequence of drug release from matrix systems. Higuchi diffusion model and the HLxon-Crowell erosion model were used to investigate the mechanism of drug release from matrix systems. Korsmeyer- Peppas equation also categorized drug release mechanisms as Fickian/non Fickian/anomalous. n1e release exponent n value is utilized in the Korsmeyer-Peppas equation to characterize distinct release processes from the dosage.

[0047] Stability studies: To examine the stability of the drug formulation, stability experiments were conducted by ICH. The optimized formulation was sealed in a polyethylene-laminated aluminium container. Samples were stored at 40 C and 75%RH for a month. The formulation was examined for any changes in its characteristic.

[0048] Kinetic analysis of release data: the optimized formulation in vitro drug release pattern was best described by first order, as the plots exhibited the maximum linearity with R1 =0.9664 Table 7. Higuchi has studied the rate laws anticipated by the various dissolving processes, both alone and in combination. The equation predicts a first order dependency on the concentration gradient between the static liquid layer near to the solid surface and the bulk liquid, similar to the other rate law equations. Noyes and Whitney employed a notion close to the diffusion model to explain their dissolution findings. The data produced by the formulation. Did not correspond well to zero order kinetics, and this model was not appropriate for explaining the rate kinetics of oral rapid dissolving film formulation. 'The data was fitted with equation, which produced n = 0.31 for formulation, howling that fickian diffusion (case J diffusional) was the mechanism of drug release.

[0049] Stability studies: According to the findings, there is no substantial change in the surface pH, thickness, folding endurance, drug content, or percentage of drug release Table 8. darexaban Oral Thin Films (OTF) were developed utilizing the solvent casting method. A full factorial design with 22 experin1ental factors was employed using Design Expert 11 software. Both independent factors and dependent variables were carefully selected.

[0050] Quantitative assessment of all samples was performed using Design Expert 11 software to determine the significant and non-significant effects of the chosen components on reactions such as Disintegration Time, Folding Endurance, and 'Thickness. 'TI1rough the use of an overlay plot and response surface plot, the optimized formulation (FS) was successfully determined.

[0051] The FT-IR spectra analysis indicated the absence of any detectable chemical interactions between the medication and the polymer. The distinctive: bands of the pure drug remained unaffected by the presence of the polymer.8 Additionally, the comparison of melting peaks in the DSC curve between rivaroxaban and the physical combination demonstrated the absence of any interaction, confirming the presence of the drug in its original, unmodified indicate that the optimized formulation FS exhibited a visually seamless and attritive surface. The wright of FS was determined using a digital balance, along with the average weight of the film. 'TI1e film thickness was measured by calculating the mean value from five different locations using a micrometre screw gauge. '

[0052] The pH of the film was found to be approximately neutral, which is considered acceptable when measured using pH paper. A similar result was obtained when the pH was measured using a pH electrode, indicating a nearly neutral pH.is the presence of propylene glycol contributed to the flexibility of the film, while the mechanical properties were attributed lo HPMC. As the concentration of the polymer increased, the percentage of moisture loss in the film also increased. However, the film was found to absorb less than 2% moisture. Therefore, it is necessary to protect the film from environmental moisture due to its tendency to absorb moisture.

[0053] The drug content and content uniformity of the film were found to be within the acceptable range defined by the pharmacopeia. 'These results indicate that the medication was uniformly distributed throughout the film. 'The disintegration time of the film was found to be influenced by the concentration of the super disintegrant. Specifically, as the concentration of the super disintegrant increased, the disintegration time decreased.27 'TI1c drug release from the film commenced immediately upon contact with the medium, and the extent of drug release was greater compared to traditional dosage forms currently available. The in vitro release pattern of the drug followed first-order kinetics, and the mechanism of drug release was identified as fickian diffusion. , Claims:Claims:
I/We Claim:
1.A process of evaluating fast dissolving oral film of rivoroxaban, comprising:
a differential scanning calorimetry thermograms of API and physical mixture was recorded by enclosing them in heat-resistant aluminium pans;
the surface of the pan lid was crimped by pushing them against a pellet mill;
the pans were held in the heating chamber to temperatures ranging from 30 to 3000C at 100C/min;
the calibration curve for rivaroxaban was developed using acetonitrile
a 100gg/mL solution is prepared;
the different concentrations of rivaroxaban at various concentrations 2, 4, 6, 8, 10 pg/mL were obtained;
a solvent casting process;
the solvent casting process involves adding HPMC E15 LV and propylene glycol to the water;
whereby keeping the temperature at 600C and the stirrer rotating at 1000 rpm;
a Color, flavoring agent, sweetening agent and disintegrant are dissolved in water with continuous stirring;
the resultant solution is combined with the API dissolved in a solvent;
wherein to extract the trapped air, a vacuum is employed;and
the homogenous solution formed is cast as a film and allowed to dry before being cut into the appropriate size.

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